Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

• Published in: Nature chemical biology Vol. 7; no. 1; pp. 41 - 50
• Main Authors: Reif, Karin, Currie, Kevin S, Di Paolo, Julie A, Huang, Tao, Balazs, Mercedesz, Barbosa, James, Barck, Kai H, Bravo, Brandon J, Carano, Richard A D, Darrow, James, Davies, Douglas R, DeForge, Laura E, Diehl, Lauri, Ferrando, Ronald, Gallion, Steven L, Giannetti, Anthony M, Gribling, Peter, Hurez, Vincent, Hymowitz, Sarah G, Jones, Randall, Kropf, Jeffrey E, Lee, Wyne P, Maciejewski, Patricia M, Mitchell, Scott A, Rong, Hong, Staker, Bart L, Whitney, J Andrew, Yeh, Sherry, Young, Wendy B, Yu, Christine, Zhang, Juan
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2011
• Subjects: Animals; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Experimental - metabolism; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Autoantibodies - immunology; Autoantibodies - metabolism; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Benzamides - chemistry; Benzamides - pharmacology; Benzamides - therapeutic use; Binding sites; Biochemistry; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cell Proliferation - drug effects; Enzyme Activation - drug effects; Inhibitor drugs; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Interleukin-6 - immunology; Interleukin-6 - metabolism; Kinases; Mice; Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - pharmacology; Protein-Tyrosine Kinases - therapeutic use; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.481

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.